Sarcoidosis is a heterogeneous, granulomatous disease of world-wide prevalence, most commonly involving the lung, skin, lymph node and eyes. Although the etiology is unknown, molecular and immunologic investigations of sarcoidosis specimens suggest that host interactions with infectious antigens, particularly mycobacterial antigens, contribute to pathogenesis among some subjects. In addition, it has been recently demonstrated that broad-spectrum antimycobactehal therapy (CLEAR regimen) provides clinical improvement among pulmonary sarcoidosis subjects without fibrosis, but not among those with advanced fibrotic disease. It is unknown if distinctions in the microbial community exist among heterogeneous sarcoidosis populations. In a similar fashion, an association has been observed between disease severity among patients with Alpha-1-antitrypsin (AAT) deficiency and pathogenic bacteria. Alpha-1 antitrypsin (AAT) is a potent antiprotease with activity against neutrophil elastase (NE). AAT deficiency is associated with a greater neutrophil load, higher elastase activity, leukotriene-B(4) concentration, and serum protein leak than matched patients without deficiency; the resultant airways inflammation with neutrophil recruitment and elastase release is positively correlated with colonizing bacterial load. Microbiome analysis of both sarcoidosis and AAT specimens will enhance understanding of the contribution infectious agents provide to disease severity. Sarcoidosis is also characterized by cellular anergy; we observed improvement in sarcoidosis T cell biologic function among some sarcoidosis subject who completed this antimycobacterial regimen, suggesting the microbial virulence factors may contribute to sarcoidosis T cell anergy. We hypothesize the distinctions in microbiota correlate with disease severity among sarcoidosis and AAT populations, and that the microorganisms present possess the capacity to induce T cell anergy. We propose to define the microbiota within heterogeneous sarcoidosis and AAT populations, and to determine the effects of the microbiome on T cell biologic function. RELEVANCE: Sarcoidosis and AAT are important medical problems. The strength of this proposal is microbial characterization according to disease severity among heterogeneous sarcoidosis and AAT cohorts. This proposal will also enhance understanding of microbial induction of T cell anergy, for which there is a lack of appreciation in idiopathic lung diseases.